Pine Pharmaceuticals, LLC — FDA Warning Letter Findings

Your firm failed to determine actual yield and percentages of theoretical yield at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product [21 CFR 211.103]. Specifically, in addition to the deficiencies noted in the visual inspection reject rate calculations, our review of the data collected during the inspection revealed that the acceptable yield range established in your batch records permits yields as low as (b)(4) , allowing up to (b)(4) of a batch to be rejected without triggering an investigation, yet the batch can still be released for distribution. Furthermore, although (b)(4) meets the definition of particulate matter as “mobile undissolved particles, other than air bubbles, unintentionally present in solutions” in SOP-061 (Visual Inspection Finished Product, Rev. 23), it was classified as a “minor” defect in ISSUE-2025-0011, without scientific justification or a clear procedural basis in SOP-061. By classifying (b)(4) as a minor defect rather than as particulate matter, (b)(4) rejects are counted only as part of the minor reject rate limit, bypassing both the major defect category trigger and the separate particulate category trigger entirely. Additionally, certain “cosmetic” defects are allowed to be returned to the batch, despite SOP-061 containing no definition, criteria, or examples of what constitutes a “cosmetic” defect, nor does it specify which cosmetic defect may be returned to the batch and which must be rejected.

Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes [21 CFR 211.113(b)].

Your response concludes that the observed aseptic technique failures were isolated to one operator and posed no product impact, with the risk declared low based primarily on passing environmental monitoring and sterility test results. However, your own batch review data (Tables 1 and 2 in ISSUE-2025-0006) demonstrates a widespread pattern of non-adherence by that operator across (b)(4) reviewed batches, with (b)(4) disinfection adherence to SOP-299 at only 11% and (b)(4) disinfection adherence at 0%. Reliance on passing environmental monitoring and sterility test results does not adequately address the significant risk created by these repeated failures to follow basic aseptic techniques, including inadequate sanitization of materials and equipment transferred from the ISO 7 area into the ISO 5 hood during production of drug products intended to be sterile. This approach is scientifically insufficient because microbial contamination does not spread uniformly, and limited environmental monitoring and finished product sterility testing cannot reliably detect low-probability contamination events from consistent (b)(4) and (b)(4) lapses. Furthermore, your claim that the process is “closed” is not supported, as aseptic operations occur in ISO 5 hoods with routine interventions, making operator technique a primary sterility assurance control. Although you stated that similar deficiencies do not exist with other operators, you provided no supporting documentation (e.g., audit reports, video reviews, or Manufacturing Quality Assurance (MQA) records) to support this claim. You also did not provide the operator removal record (AI-2025-0524), the revised SOPs under CAPA-2025-0015, or a defined effectiveness verification plan. The repeated nature of these deviations by the same operator, going undetected and uncorrected over an extended period, raises serious concerns about the effectiveness of your routine oversight, training reinforcement, and overall quality system controls. The failures to sanitize or change gloves and sleeves after contact with non-sterile ISO 7 surfaces, and the failure to sanitize materials and equipment transferred from ISO 7 into the ISO 5 area, are not minor risks. They constitute insanitary conditions which can lead to contamination of products intended to be sterile and serious adverse events. Your response also fails to explain why these deviations went undetected for so long and does not address the specific hand sanitization deficiencies noted in the observation, including incomplete coverage of the backs of the hands and interdigital spaces and failure to meet the required (b)(4) duration as per your SOP-299 (Cleanroom Behavior and Aseptic Technique Procedure, Rev. 04). This is a repeat deficiency from the FDA inspections conducted in May 2021, September 2023, and September 2024.

Your response fails to address the specific deficiencies in the cited investigations and non-conformances. For the particulate complaint (COMP-2025-0005), your firm did not determine root cause for the confirmed cellulose particles or translucent fibers found in the returned vials or the retain sample, reconcile the particulate finding in the retain sample with the multiple particulates observed in the returned vials, or implement corrective actions for the visual inspection failure that allowed particulates to reach distributed product. You classified cellulose as an “intrinsic” particle without scientific justification, despite potential sources (e.g., cleaning wipes) indicating extrinsic contamination. Your response does not clearly commit to identifying and characterizing all observed particulates (including fibers and residues) in future investigations, nor does it define when such identification is required. Additionally, although you revised POL-030 (Product Complaint Handling) and implemented a training checkpoint, you did not provide evidence that the training was completed and did not establish a defined effectiveness verification plan for these corrective actions. For the batches released despite exceeding critical defect limits, your responses rely on retrospective risk assessments, passing targeted/second 100% reinspection and (b)(4) AQL without thorough root-cause investigations or (b)(4) process corrections for recurring defects (e.g., dislodged caps, partially crimped seals, particulates). These risk assessments are outcome-based, focusing primarily on the absence of complaints or adverse events rather than evaluating the adequacy of your production and inspection controls. Furthermore, lot disposition for batches exceeding the (b)(4) critical reject rate was contingent on the outcome of a pending risk analysis (ISSUE-2025-0008) rather than on a completed investigation and upstream correction, indicating that risk assessment is being used as a substitute for corrective action rather than a complement to it. You also provided no scientific justification for limiting reinspections to preselected defect types rather than conducting a comprehensive 100% visual inspection across all potential defects, and you provided no evidence that CAPA-2025-0017 has been completed. This pattern of relying on reinspection and risk review to achieve passing results, without addressing underlying process failures, fails to demonstrate that the root causes of these defects have been identified, addressed, or controlled.

Your response states that you conducted a historical review of qualification records and provided additional training for visual inspectors. However, you failed to manage the significant change to SOP-155, Training and Qualification of Qualified Visual Inspectors for Compounded Products, Rev. 09 (which introduced immediate failure of a visual inspector for missing any critical defect) through formal change control or a timely requalification plan for previously qualified inspectors that did not meet the new standard. You did not perform a root-cause analysis for why inspectors continued performing critical visual inspections for approximately three months after the SOP revision without meeting the new standard. Although you dispute the specific example with visual inspector (b)(6), (b)(7) , you provided no documentation reconciling the answer key discrepancy or addressing the violation of performing (b)(4) qualification assessments in (b)(4) . You also submitted no evidence that all impacted inspectors have been removed from relevant tasks or successfully requalified under the revised criteria. In addition, you have not committed to managing future significant changes to qualification procedures through formal change control. CAPA-2025-0014 remains pending with no supporting documentation.

Your response states that you reviewed (b)(4) batches and implemented PLANDEV-2025-0027 to include all rejected units (confirmed and unconfirmed) in reject rate calculations. Although you identified six batches that would have exceeded thresholds when using actual reject rates, you did not demonstrate that formal investigations were opened for these batches. In addition, the permanent updates to SOP-061 (Visual Inspection Finished Product, Rev. 23) and the electronic batch record remain incomplete, with no firm completion dates or effectiveness verification plan. You also did not address the specific Diltiazem HCl lot 83709 example discussed during the inspection close-out. This is a repeat deficiency from the FDA inspection conducted in September 2024.

Your response states that you implemented post-production surface sampling of (b)(4) per FID 131 batch (PLANDEV-2025-0021) and plan to transition to (b)(4) trays by the end of Q2 2026. While these actions are intended to address the observed deficiency, we are unable to determine their adequacy due to insufficient supporting documentation and scientific justification. You did not provide data demonstrating the effectiveness of (b)(4) for cleaning the current trays (particularly the difficult-to-clean (b)(4) ), a risk-based rationale for sampling only (b)(4) when (b)(4) bins are used per lot, justification for the chosen sampling site, confirmation that tray sampling will be permanently incorporated into routine procedure MWA-041, a validation protocol for the planned (b)(4) trays, or a defined plan to verify the effectiveness of the interim tray sampling program. Some of your corrective actions appear deficient…

Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 CFR 211.192].

Your response acknowledges the lack of validated mixing and (b)(4) parameters but treats full process validation (CAPA-2025-0013) as conditional, only to be prioritized if future potency variability or out of specification (OOS) events occur. You provided no root-cause analysis explaining why critical process parameters remained undefined and operator-dependent for an extended period despite a prior OOS investigation. You also submitted no supporting documentation for PLANDEV-2025-0028, no revised master production records or executed batch record examples showing the new parameters, and no completion date or detailed validation plan for CAPA-2025-0013. In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you produce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b).] FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. In particular, this review should assess your aseptic processing operations. A third-party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation. D.

Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)]. Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a revised draft guidance, Current Good Manufacturing Practice — Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act . This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated. Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being adulterated. C. Corrective Actions We have reviewed your firm’s responses to the Form FDA 483. We are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation…

Your firm did not disinfect materials during transfer from the ISO 7 cleanroom into the ISO 5 hood. Specifically, operators failed to sanitize materials, equipment, and hands prior to introducing them into the ISO 5 critical area during the production of drug products intended to be sterile. Furthermore, an operator rested their sleeved arms on ergonomic support bars attached to the ISO 5 hood (located in the ISO 7 background area) and subsequently extended their sleeved arms into the ISO 5 critical area without first sanitizing their sleeves.

Your environmental monitoring program lacks adequate routine environmental monitoring that captures data representative of aseptic production conditions. Specifically, your firm does not perform routine environmental monitoring of high-touch staging trays ( (b)(4) ) that are manually handled by gloved operators to stage materials, including final container closures for drug products intended to be sterile, prior to placement into the ISO 5 classified area. These trays have a difficult-to-clean (b)(4) design. FDA investigators also collected evidence indicating CGMP violations at your facility, that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example…

Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions [21 CFR 211.25(a)].